The overarching goal of this K99/R00 proposal is to further the candidate's expertise in the immunological bases of persistent pain conditions and their co-morbidity with depressive symptoms. More specifically, the candidate seeks to develop expertise in the utilization of PET neuroimaging techniques as an investigational tool in understanding the role of immune factors in the pathophysiology of chronic pain states such as Fibromyalgia (FM). Such research is well positioned to discover the mechanisms underlying many mind-body interactions in chronic pain states like FM. Candidate: The candidate's education and training thus far have prepared him well for the proposed grant. A Clinical Lecturer of Psychiatry at the University of Michigan, the candidate is trained as an engineer, psychiatrist, and PET neuroimager with an evolving research interest in the role of inflammatory cytokines in depression and pain states. As such, he is well poised to advance patient-oriented psychoneuroimmunology research. However, to achieve full research independence and obtain a competitive tenure track faculty position, he has defined specific areas requiring further/supplemental training: 1) chronic pain research, 2) innate immune functioning (enhancing practical cytokine assay skills), 3) advanced statistical techniques, and 4) PET neuroimaging advanced analytic techniques. Environment: The candidate will benefit from established collaborative relationships between researchers in psychiatry and other departments at the University of Michigan (i.e., Radiology, Michigan Institute for Clinical and Health Research, Center for Statistical Consultation and Research). The candidate has access to PET and MRI scanning facilities, cytokine assay labs, and a wide range of clinical samples. Dr. Jon-Kar Zubieta, the candidate's primary mentor, has an established record as both mentor and productive neuroscientist with 15 years of expertise in PET neuroimaging of depression and pain. Two additional internal mentors, Drs. Daniel Clauw (pain) and Alisa Koch (immunology), and one external mentor, Dr. Steven Zalcman (behavioral consequences of cytokine challenge), will round out the mentorship team. Consultants, one external (Dr. Andrew Miller) and two internal (Dr. Robert Koeppe and Dr. Edward Rothman), will provide expert consultation in using TNF-alpha antagonists (i.e. etanercept) as an inflammatory challenge, PET neuroimaging physics, and statistical methods, respectively. Research: Spanning the award duration, the proposed research plan focuses on determining the role of inflammatory cytokines in the pathophysiology of chronic pain states (i.e. FM). FM is a common, debilitating illness, and a significant public health concern. Etanercept, a cytokine (i.e. TNF-alpha) antagonist, is proposed as a mechanistic probe to differentiate causality from epi-phenomena in determining the role that cytokines play in the dysregulaton of central mu-opioid receptor mediated anti-nociceptive mechanisms in FM. Current understanding of the biological underpinnings of FM is marked by equivocal findings. Some data suggest the underlying dysregulation in FM is central, such as a down-regulation of mu-opioid receptor mediated neurotransmission, while other data suggest dysregulated peripheral nociceptive mechanisms involving pro-inflammatory cytokines. Preliminary data suggests that both peripheral and central mechanisms are involved, and further, interact with each other, potentially perpetuating the persistence of pain. Indeed, pro-inflammatory cytokines (i.e. TNF-alpha, IL-1beta) are implicated in hypernociceptive states (i.e. pain hypersensitivity in FM) in humans and animal models. Pro- inflammatory cytokine antagonists (i.e., etanercept), have been shown in animal models to reverse this hyper-nociceptive state. However, in-vivo human research is limited by the lack of available research paradigms to mechanistically unravel the underpinnings of FM. Preliminary data shows that pro-inflammatory cytokines are associated with activation, and potential dysregulation of central mu-opioid neurotransmitter function in pain states, depression, and in response to pain and emotional stress. These data specifically implicate the ventral striatum and amygdala, regions involved in encoding salient and stressful signals, rewarding and aversive. Further, these data implicate anti-inflammatory cytokines (i.e. IL-1ra,sTNF-alphaR1) as having opposing effects on mu-opioid receptor availability in vivo in these same regions. However, differentiating causality from epi-phenomena is a necessary step in translation to novel treatment strategies. Given its direct and indirect action on inflammatory cytokines central to rheumatological processes, and the data illustrating cytokine involvement in hypernociceptive states and central opioid functional measures, etanercept is ideally suited to this task. Specific AIMS: Aim 1: To determine the presence of moderate sustained pain stress induced changes in central MOR mediated neurotransmission (and peripheral inflammatory state) in chronic pain. Aim 2: To show that lower baseline MOR BPND (and higher pro-inflammatory cytokine concentrations) will predict response to etanercept pre-treatment, in FM. Summary: This K99/R00 proposal is well aligned with missions of the NIH (PA-10-006: Mechanisms, Models, Measurement, & Management in Pain Research). The project will provide a promising junior investigator with additional training requisite to his traversal to independence as a clinical translational psychoneuroimmunologist. Simultaneously, the project will address important, testable questions regarding the poorly understood mechanistic underpinnings of acute and chronic pain states such as FM. PUBLIC HEALTH RELEVANCE: The proposed K99/R00 project serves dual purposes: (1) to expand the research training of a promising physician-scientist to become an independent investigator in psychoneuroimmunology research of chronic pain states, and (2) to utilize etanercept, an anti-inflammatory medication, as an inflammatory probe, artificially altering the circulating inflammatory cytokine milieu, discerning causality from epi-phenomena in the relationship between cytokines and mu-opioid functioning in pain states. Accomplishment of these two objectives will address the recognized shortage of physician scientists that are pursuing translational psychoneuroimmunology research in chronic pain states, and will simultaneously answer clinically relevant questions about common, disabling illnesses that too often fail to respond to current treatments.